The CDC and WHO have declared Sickle Cell Disease (SCD) a public health priority. In the U.S. alone, some 100,000 patients suffer with SCD, with annual healthcare costs estimated at $1.1 billion. SCD patients have a mutant form of hemoglobin (Hb) that can change the shape of their red blood cells (RBCs) and cause the cells to clump together and stick to vessel walls, resulting in blocked blood flow that causes extreme pain, heightened stroke risk, and organ damage. The prognosis for SCD patients is grim. Pain crises and other complications require frequent ER visits and hospitalizations. Current SCD healthcare options primarily treat complications via antibiotics, psychological support, pain management, intravenous fluids, blood transfusions, palliative drugs, and surgery. However, fetal hemoglobin (HbF) - which normally drops soon after birth - shows promise as a therapeutic target. Numerous studies indicate that higher HbF levels result in decreased SCD complications. Epidemiological and lab studies have shown that reconstitution of HbF levels to 25-30% is sufficient to ameliorate SCD symptoms. Yet, the only available FDA-approved pharmaceutical HbF inducer, hydroxyurea, does not achieve the HbF levels required to prevent symptoms and is associated with a number of side effects. Achieving a consistent level of at least 25% HbF in patients is expected to enhance patient quality of life by alleviating symptoms, eliminating pain crises, and increasing lifespan. The goal of this Phase I SBIR project is thus to demonstrate that our candidate drug, EdX-17, can reconstitute HbF to levels e25% safely (without significant side effects). Preliminary work done by the interdisciplinary EpimedX team demonstrates that EdX-17 can produce 30-50% HbF in mice and supports this approach (Section 3.3). For this Phase I feasibility project, EpimedX will pursue three Aims: 1) establish a dose-response relationship between EdX-17 levels and HbF expression in vitro; 2) determine the time dependence of HbF production with EdX-17 treatment in vitro; and 3) establish the feasibility of achieving e25% HbF expression with EdX-17 treatment in vivo. This project will provide data to address the key research question: Can we demonstrate that daily EdX-17 treatment enhances endogenous production of HbF to therapeutic levels for SCD treatment with low toxicity within 30-90 days in vivo? Phase I success will lead to a larger Phase II project focused on FDA- required toxicology studies in preparation for an IND and human clinical trials in Phase III. The R&D team for this project includes PI Dr. Robert Broyles (EpimedX founder/CSO and President of the Sickle Cell Cure Foundation), a 40-year pioneer in sickle cell research; co-founder Dr. Robert Floyd (COO), who helped found and manage two other biotech companies (Centaur Pharmaceuticals and Otologic Pharmaceutics); and a team of seasoned technical experts and biotech investors. Development/commercialization of this novel therapeutic is expected to ameliorate SCD symptoms-decreasing pain and morbidity, increasing lifespan, greatly improving patient quality of life, and significantly reducing treatment costs.